Orforglipron is a non-peptide glucagon-like receptor-1 (GLP-1R) agonist that can be orally administered once daily irrespective of food intake. Different doses of oeforglipron were evaluated in two phase 2 clinical trials including subjects with obesity and type 2 diabetes, respectively. In the obesity trial, subjects with mean baseline weight of 108.7 kg and body mass index (BMI) of 37.9 kg/m2 had 9.4% to 14.7% of weight loss at 36 weeks compared with 2.3% loss with placebo. In the diabetes study, glycated hemoglobin (HbA1c) levels (baseline 8.1%) decreased from 1.2% to 2.1% in the orforglipron groups, 1.1% with dulaglutide (1.5 mg/week), and 0.5% with placebo at 26 weeks. In the latter trial, mean weight loss at week 26 was 3.7% to 9.6% with orforglipron, 4.0% with dulaglutide, and 2.2% with placebo. While HbA1c reduction seemed to reach a plateau at 20 weeks, weight loss continued to progress up to the end of follow-up at 36 weeks. In general, safety profile of orforglipron resembles that of GLP-1R agonists with gastrointestinal (GI) adverse effects being the most common. Yet, premature discontinuation rates were high; 19.1-21.1% across the orforglipron groups compared with 4% with dulaglutide and 2.0-5.5% with placebo. In addition, there was a pronounced increase in heart rate with the use of orforglipron; placebo-adjusted increase being 7.7-9.2 beats per minute (bpm). Overall, orforglipron is a promising oral GLP-1R agonist for treatment of obesity and type 2 diabetes. Phase 3 trials are urgently needed to clarify its long-term efficacy and safety.   

Currently, the peptide semaglutide (Rybelsus) is the only oral GLP-1R approved for treatment of type 2 diabetes [1]. However, oral semaglutide is limited by strict criteria of intake that may potentially limit compliance. Thus, it must be taken in the fasting state with no more than 4 ounces (120 cc) of plain water at least 30 minutes before the first food, beverage, or other oral medications [1]. Several orally administered non-peptide GLP-1R agonists are under development for treatment of obesity and type 2 diabetes, orforglipron being the most studied so far [2,3]. Contrary to oral semaglutide, orforglipron may be taken orally once a day irrespective of food or water intake. Results of phase 2 clinical trials suggest that orforglipron may be an effective anti-obesity and anti-diabetic agent [2,3]. The main purpose of this review is to provide an appraisal on orforglipron with respect to its efficacy and safety profile.

Orforglipron for treatment of obesity: 

Orforglipron was evaluated in various doses [12, 24, 36, 45 mg/d]. in a randomized phase 2 double-blind, placebo-controlled trial of 272 obese subjects (59% women, mean age 54.2 years, mean weight 108.7 kg, mean BMI 37.9 kg/m2) [2]. The starting dose and titration schedule varied between groups. Throughout the trial, education regarding healthy eating and exercise was provided to all enrolled individuals [2]. The primary and secondary endpoints of the trial were the percentage change from baseline in weight after 26 weeks and 36 weeks respectively [2]. At week 26, the mean change from baseline ranged from -8.6% to -12.6

Orforglipron represents a new class of non-peptide GLP-1R agonists that can be taken orally once a day without food or water restrictions. Other non-peptide GLP-1R agonists, such as danuglipron, are under development [9]. Phase 2 trials lasting 26-36 weeks show that orforglipron cause an average placebo-adjusted substantial weight loss of up to 12.4% and 9.6% in subjects with obesity and type 2 diabetes, respectively [2,3]. A second phase 2 trial suggest that orforglipron is effective as antihyperglycemic agent causing an average reduction of HbA1c levels of up 1.7% [3]. The magnitude of decrease in weight and HbA1c values are close to those achieved by the highest dose of oral semaglutide (50 mg/d) shown in phase 3 clinical trials (table 1). In general, safety profile of orforglipron is comparable to that of the class of GLP-1 agonists. Yet, the incidence of GI adverse effects may be higher with orforglipron compared with other GLP-1R agonists, in part due to patterns of dose initiation and escalation. The latter observation may explain the high rates of orforgliflozin discontinuation due to adverse effects reaching up to 21% (versus 5.5% with placebo) (table 1).

Abbreviations in the table: GLP-1R: glucagon-like peptide-1 receptor, FDA: Federal Drug Administration, HbA1c: glycated hemoglobin, bpm: beats per minute. 

Table 1: Comparison between orforglipron and oral semaglutide

Furthermore, the increase in placebo-adjusted heart rate of 7.7 to 9.2 bpm with orforglipron appears to be more pronounced than other GLP-1R agonists.  Phase 3 clinical trials are underway to clarify efficacy and safety of orforglipron in larger patient population of obesity and type 2 diabetes from different ethnic backgrounds. The changes in heart rate and any types of arrhythmias should be included as pre-specified adverse effects in these trials. More importantly, the effects of orforglipron on cardiovascular events and mortality should be evaluated in adequately powered long-term trials. In addition, direct comparison of orforglipron with oral semaglutide should be studied in the setting of double-blind trials. 

The author has no conflict of interest to declare.